This is a competitive renewal from Dr. Rafi Ahmed to study T cell memory to viruses. Immunological memory is the ability of the immune system to respond with greater vigor upon re-encounter with the same pathogen and constitutes the basis of vaccination against infectious diseases. A better understanding of immunological memory is critical for the rational design of vaccines. This proposal examines the mechanisms that regulate the generation and maintenance of CD8 T cell memory to viruses. CD8 T cells play a critical role in controlling viral as well as intracellular bacterial and parasitic infections and are also of importance in immunity against tumors. Aim 1 will characterize the global reprogramming of gene expression that accompanies memory CD8 T cell differentiation using DNA microarray technology. A global view of changes in expression of genes with known functions could provide a vivid picture of the biochemical mechanisms that produce accelerated response to antigen and longevity in memory CD8 T cells. With the recent breakthroughs in our ability to isolate pure populations of antigen specific naive, effector and memory CD8 T cells, and the development of DNA microarray technology, it is now possible to monitor genome-wide expression in antigen specific CD8 T cells. Aim 2 will investigate the mechanisms that regulate homeostatic proliferation and maintenance of memory CD8 T cells. It is now well established that memory T cells undergo a slow proliferative renewal. The experiments proposed in this aim will attempt to characterize the nature of this homeostatic proliferation and to understand how it is regulated. The investigator believes that understanding the regulation of homeostatic proliferation is the key to understanding memory T cell maintenance and the studies proposed in this aim should provide insight into this important issue. Aim 3 will compare on a per cell basis the ability of memory CD8 T cells induced by different antigen delivery systems to confer protective immunity. Protective immunity is the essence of immunological memory and this aim addresses a crucial biological question about memory T cells; namely, are memory CD8 T cells induced by different vaccine regimens equally good at protective immunity against viral infection. The fact that different vaccines generate different numbers of memory CD8 T cells has been long appreciated and is usually considered to be the primary, if not the sole reason, for varying levels of protective immunity induced by different vaccines. The qualitative aspects of vaccine induced memory T cells have not received much attention. The experiments proposed in this aim will address this specific issue. The goal of this aim is to determine what type of vaccines generate optimal memory CD8 T cells.